Despite strong virus-specific humoral and cellular immune responses, disease progression ensues in the vast majority of HIV infected individuals indicating that the host immune response is typically unable to control infection. Understanding the failure of these immune responses is a central component in understanding HIV pathogenesis and developing strategies for effective vaccines and immune based therapies. Virus-specific T helper cells are critical for the maintenance of effective immunity in most chronic viral infections, however in the majority of HIV infected individuals, these cells are weak or absent in all stages of disease and represent a major defect in the immune response against this virus. HIV-specific T helper cells perform an essential role in the control of HIV replication through the collaboration with cytotoxic T lymphocytes, neutralizing antibody and possibly via direct antiviral effects. However our understanding of these critical immune responses is far from complete and the reason why some infected individuals control HIV replication while others do not is unclear. The goal of this proposal is to perform an in-depth characterization of HIV-specific T helper cell responses in an attempt to further our understanding of the relationship between HIV-specific T helper cells and the pathogenesis of infection. Specifically, we propose: 1. To determine the evolution of HIV-specific T helper cell responses in terms of the magnitude, breadth, specificity and functionality in persons who maintain control of viremia and in persons who lose control of viremia. 2. To determine the precise epitopes targeted by HIV-specific T helper cells as well as the restricting class II alleles, using unique cohorts of persons with acute/early HIV infection and in persons with long-term spontaneous control of viremia. 3. To determine whether sequence variation within HIV T helper cell epitopes leads to functional immune escape.